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Nobel Lecture

Antineuritic Vitamin and Beriberi

Beriberi is a disease prevalent,
epidemically, in tropical and subtropical regions of Eastern
Asia, where rice is the staple food of the natives; it is found
elsewhere among sago-eating peoples (Molucca Islands), as well as
in South America, in places where rice or cassava meal is the
staple diet, as in certain parts of Brazil. However, the disease
also occurs sporadically - here and there even with abundant
frequency - in the temperate zone and, in some circumstances, in
the frigid zone.

The symptoms of the disease are paralysis
and numbness starting from the lower limbs, as well as cardiac
and respiratory disorders accompanied by dropsy. These latter
symptoms rapidly come to the fore, and we then speak of "wet
beriberi". Soon the motility and sensitivity disturbances,
eventually accompanied by severe muscular atrophy, become more
pronounced ("dry beriberi"). Mixed and transitional forms,
however, are not rare. Where the paralysis is fairly advanced,
the peculiar gait of the patient is noticeable. As the extensors
of the foot are paralysed, the patient has to raise the knee up
and swing the foot forward in order to avoid stumbling over the
downhanging toes.

It is mostly young men in full vigour who
are stricken by the acute form of the disease; they not
infrequently die suddenly, in terrible distress through inability
to breathe. This fatal issue, even in the more chronic cases, is
often due to intercurrent causes, e.g. physical strain, or
diseases such as malaria, dysentery, etc.

Although beriberi was described as long ago
as in the first half of the 17th century by the Dutch specialist
in tropical medicine Bontius, it has only shown itself as a
really devastating disease in the Malay Archipelago since about
the sixties of last century, and then generally speaking not so
much among the free population as among people living to some
extent under constraint, such as soldiers, sailors, prisoners,
imported coolies in the mines and plantations, and so forth. It
was particularly common in the native prisons; even detainees
awaiting trial, sometimes died of the disease. And in the native
hospitals it claimed many a victim among people admitted for a
relatively minor ailment, such as gonorrhoea or a fractured
bone.

During the protracted war - a true guerilla
war - which we had to wage with the Achin sultanate, both army
and navy suffered very severely from the disease. Newly drafted
native troops were often unfit for service after about six weeks
and the pitiful remnant had to be evacuated as quickly as
possible. For instance, a man might apparently be in good health
in the morning, and even gave proof of his skill during target
practice, and then fell victim to the disease by evening. An army
doctor of that time mentions that at his hospital 18 soldier died
of beriberi on one day.

European troops also suffered from the
disease in Achin, though to a lesser extent than the native
troops.

Faced with this serious situation, the Home
Government decided in 1886 to send out a commission to
investigate the nature of beriberi and its cause. Pekelharing,
Professor of Pathology, and Winkler, reader in neurology, both of
the Medical Faculty of the University of Utrecht, were in charge,
and I was seconded to the commission as an assistant. Winkler
immediately established that the disease was essentially a form
of polyneuritis (more accurately: multiple neuratrophy), a
finding which agreed with results obtained by Bälz and von
Scheube from investigations conducted by them in Japan. The
clinical symptoms were also consistent with this
pathological-anatomical diagnosis, which moreover could be
confirmed in the living subject by electrical examination
(reaction of degeneration, etc.).

At that time there were naturally many
different theories as to the cause of beriberi. Two of these were
based on the fact that the disease was particularly prevalent
among rice-eating populations, although -as already mentioned -
this is not always the case. On the one hand, rice poisoning was
suspected; on the other, a deficiency of the rice diet, but not
in the same sense as we now understand it.

With regard to the first theory, the
disease was found to occur all too often where the rice was of
excellent quality from the culinary point of view. Neither was
any actual proof of a preexisting poison in the rice diet found,
or even sought. This also applies to other poison-theories, e.g.
that the disease was due to rotten fish or to "mephitic" gases
emanating from the soil.

The second theory was formulated by Van
Leent in 1879 in the light of his experience with the East Indies
Navy. He considered that an one-sided rice diet resulted in
malnutrition owing to its very low content of protein and fat,
and that this condition would promote beriberi. He found that the
incidence of the disease among native sailors fell considerably
when they were put on to a European diet.

There were weighty arguments against this
theory, in particular the fact that people with great muscular
strength and a welldeveloped panniculus adiposus were
often attacked by the disease; and also that European crews, on a
diet containing sufficient protein and fat, were not immune, even
when they were given virtually no rice at all. In the report made
after its return to Holland, the commission rejected this theory
because it could not be assumed that malnutrition in itself would
result in destruction of peripheral nerves. For this a directly
injurious effect on the nerves or their centers would be
necessary. In the light of our knowledge today, however, we see
that there was a very large grain of truth in Van Leent's theory,
and it can scarcely be doubted that a lasting improvement in the
health of the native crews could have been achieved if it were
possible to introduce the Dutch navy food and persuade the men to
take it. It is however a very delicate matter to alter the diet
to which people have been accustomed from their youth, and
consequently with few exceptions the native sailors soon forsook
pea soup with sausage and bacon, potatoes, bread with cheese,
etc. and went back to the monotonous and poor rice diet, which
they were usually able to procure.

Takaki, who - for reasons similar to those
of Van Leent - a few years later changed the diet of the Japanese
Navy to the European style, thereby - it is reported - achieving
lasting success in the fight against beriberi, also had to admit
that this measure was difficult to put into effect. "By last
year's experience," he said, "we have found that most of the men
dislike meat as well as bread and we do not know what we shall do
next."

However this may be, we failed to check the
disease permanently, although at first it did seem to subside a
little. But this diminution does not prove much since in any case
beriberi was subject to considerable periodic fluctuations, apart
from the fact that the statistics on the disease were not very
reliable. For instance it was quite obvious that these statistics
frequently included cases of palpitations of the heart, oedema of
the feet, as well as a new cause of death described as "hydraemia
perniciosa tropica" - conditions which should obviously have been
ascribed to beriberi. In those days diagnosis of beriberi was
clearly taboo.

In the limited time which the commission,
for official reasons, had at its disposal it was unable to carry
out experimental investigations in every conceivable direction,
and it is not surprising that at a time when bacteriology was
all-triumphant under the leadership of Pasteur and Koch, the commission
should have decided first of all to apply the methods of these
two men to the problem in hand. It had all the more reason to
take this line since beriberi is a disease with pronounced local
and periodic tendencies (as defined by von Pettenkofer). The
periodic fluctuations, the prevalence under certain climatic and
weather conditions, the epidemic occurrence in certain countries
and places, the association with buildings, and finally the cases
of transmission of the disease described in the literature - all
this pointed to an infection. True, under these circumstances a
parasitic disease might have been considered -in particular
hookworm, widely spread in the tropics, has been accused of being
the main cause of beriberi - but the commission was able to
establish that anaemia of any severity is not one of the
characteristics of this disease.

I shall not dwell on the results of the
bacteriological investigations because they have long since
ceased to have any significance, although at that time they were
apparently of fundamental importance. Polymorphic bacteria were
found in the blood of patients, although not regularly, and
degeneration of the nerves could be induced in animals by
repeated injections of a coccus culture from them. In its report,
following its return to Holland, the commission suggested very
tentatively that the cause of beriberi had thus been discovered.
The commission succeeded in isolating a coccus, which it
considered identical with the above-mentioned one, from the air
in barracks which, from its point of view, could be regarded as
infected.

Following the departure of the commission I
was entrusted with the task of continuing its investigations, but
at frost I failed to get any further. The disinfection measures
which, as is logical, were recommended had not the hoped-for
success. Then a chance happening put me on the right track.

A disease, in many respects strikingly
similar to beriberi in man, suddenly broke out in the
chicken-house at the laboratory in Batavia, and this called for a
thorough study. The symptoms of this disease are as follows: The
initial stages, following defective evacuation of the crop some
days earlier, are characterized by an unsteady gait. The bird has
difficulty in perching and has to exert itself in order not to
fall; the legs are spread through weakness, and the knee and
ankle joint are bent. The bird frequently collapses and falls
over when walking. Finally it remains lying on its side and
paresis of the wing muscles now becomes obvious from its vain
efforts to get up. Paralysis of the body muscles advances rapidly
from below. Within a few days the condition of the bird has so
deteriorated that it can no longer eat anything without
assistance; although swallowing movements are still produced, the
bird is unable to lift its head. Symptoms indicating the onset of
paresis of the respiratory muscles then appear. Respiration is
slowed down, the beak opens, comb and skin become cyanotic, the
neck is bent back and the head drawn in. The bird now becomes
more and more soporific, the eyes are covered by the nictitating
membrane and the body temperature falls a degree or two
centigrade below normal.

This was a case of polyneuritis, as
indicated by the symptoms and course of the disease and proved
beyond question by a microscopic examination.

With regard to the etiology, our original
supposition was not confirmed, i.e. that in the case of the
strikingly epizootic occurrence of the disease an infection was
involved. Attempts to induce the infection with material from
affected birds or from birds which had died of the disease were
inconclusive since all the chickens, even those kept separate as
controls, were affected. No specific micro-organism or any higher
parasite was found.

Then suddenly the disease cleared up and we
were unable to continue our investigations. The affected chickens
recovered and there were no new cases. Fortunately suspicion fell
on the food, and rightly so, as it very soon turned out.

The laboratory was still housed
provisionally and in a very makeshift manner at the military
hospital, although it was administered by the civilian
authorities. The laboratory keeper - as I afterwards discovered -
had for the sake of economy fed the chickens on cooked rice which
he had obtained from the hospital kitchen. Then the cook was
replaced and his successor refused to allow military rice to be
taken for civilian chickens. Thus, the chickens were fed on
polished rice from 17th June to 27th November only. And the
disease broke out on 10th July and cleared up during the last
days of November.

Deliberate feeding experiments were then
conducted in order to check more thoroughly whether or not the
propable connection between diet and the disease actually
existed. It was found for certain that the polyneuritis was due
to the diet of cooked rice. The chickens were attacked by the
disease after 3-4 weeks, and in many cases somewhat later,
whereas the controls which were fed on unpolished rice remained
healthy. In many cases, birds suffering from the disease could be
cured by a suitable alteration in diet.

This difference between polished and whole
rice did not lie in the fact that the former had not kept so well
during storage, since cooked rice which had been freshly prepared
from the whole kernel would also cause the disease. In addition
to this, rough rice, i.e. rice with only the coarse husk removed,
which deteriorates much more easily (being attacked by mites,
mould fungi, etc.), proved harmless during the feeding
experiments. This rice, as obtained simply by stamping, still has
its inner hull - known as its "silver skin" (pericarpium) - and
germ wholly or largely intact. We were then able to conclude from
a series of highly varied experiments that the antineuritic
principle is situated mainly in these parts of the rice kernel,
and indeed of any cereal grain. It can easily be extracted with
water or strong alcohol and is dialysable. I also established
that it can be used medicinally either through the mouth or
parenterally.

Feeding with other Amylaceae, such as sago
and tapioca, had exactly the same results as cooking rice. Since
these contain only traces of primary nutrients other than starch,
it was impossible to dismiss out of hand the suspicion that the
disease was due to simple inanition, especially as it was
accompanied by considerable emaciation. And at that time - when
the effectiveness of minute doses of the antineuritic principle
had not yet been established - the fact that the affected birds
recovered when fed on a diet consisting only of meat, could be
regarded as being tantamount to the result of an experimentum
crucis. On the other hand, by adding meat to the starch-rich diet
it was possible to prevent the emaciation but not outbreaks of
the disease, even though these were somewhat delayed. Thus,
inanition in itself could not be the main cause of the disease
(any more than "protein" or "salt" deficiency), even though it
promoted it. I also concluded from this that an antineuritic
principle must have been present in the meat, i:e. in the animal
organism, but that this principle was gradually used up while the
chickens were being fed on a starch diet. And finally the outcome
of these experiments was encouraging for me in that one apparent
difference as compared with human beriberi had thus been
eliminated, for, as already stated, beriberi not infrequently
attacks well-fed, strong individuals. Starvation experiments
which I conducted at that time also produced a negative result.
This was confirmed many times over (Holst, Shiga, & Kusama;
Fraser & Stanton, et al.) before I resumed these experiments
(in Holland) in view of a communication from Chamberlain et al.
(1911) that they had observed in 3 out of 8 cases, polyneuritis
among chickens which had been given drinking water without any
solid food. This time I obtained a positive result in no less
than six out of eight cases. However, it could not be concluded
from this alone that the cause of the disease was general
inanition, for, apart from the fact that total starvation
includes partial starvation, we were able to show that the
starved birds which were suffering from the disease, just as
birds which had been fed on an unbalanced diet, recovered again,
despite continuing loss of weight, when given 8-10 g vitamin-rich
yeast per day.

Investigations with other animal species on
the East Indies showed that birds such as pigeons and the Indian
rice bird can also be used with success. In contrast, results of
experiments with mammals were almost entirely negative. This
disappointment could, of course, not prevent me from testing
whether and to what extent the discovery which had been made as a
result of the study of polyneuritis in birds could be used in the
fight against human beriberi, although at that time there was
still reason enough to doubt the identity of the two diseases. I
was therefore accused of not being logical, a reproach which I am
happy to pass over without comment.

The obvious thing to do was to test the
preventive and curative effect of rough rice in the case of
beriberi by means of experiments and controls. Rough rice is the
staple diet wherever the rural population in the Indies grows
rice for its own use and shelled it by primitive methods. White,
or polished, rice is processed mechanically and is one of the
blessings of European civilization, of our improved techniques
which, for instance, have also changed the colour of bread here
in Europe from brown to white. Thought-provoking too was the
fact, already referred to, that the free population, which fed
itself, was much less subject to beriberi than the population
whose freedom was restricted, and which was often dependent on
imported and therefore mechanically processed, polished, rice.
(As already noted, rough rice is unsuitable for prolonged
storage.)

When the projected nutritional experiments
on man had just begun, an observation was made by Vorderman which
had almost the value of a check experiment. As civilian medical
inspector for the island of Java he knew that, in accordance with
local custom, the native prisoners were given polished rice in
some areas, but rough rice in others. The question, therefore,
was to ascertain whether there was a connection between the
nature of the staple diet and the incidence of beriberi at the
prisons. This on-the-spot investigation was carried out by
Vorderman at my request, on behalf of the East Indies Government,
and at the same time attention was paid to other factors - apart
from diet - with a bearing on the subject. As a result of this
research, conducted with admirable proficiency and perseverance,
my theory based on the chicken experiments was proved correct.
The enquiry covered no less than 101 prisons with almost 300,000
inmates. In brief, the proportion of cases of beriberi in the
prisons where polished rice was used as staple diet was some 300
times greater than in those where rough rice was used.

Vorderman's remarkable results did not at
once find recognition and were received with scepticism and
adverse criticism in some quarters. For me, who had meanwhile
been repatriated, the results agreed so unequivocally with those
of the chicken experiments that the possibility of coincidence
could not seriously be considered. However, the nutritional
experiments on which I had already embarked were discontinued,
and the alteration in the catering regulations for prisoners,
suggested after my departure by Vorderman and Grijns, in the long
run did not meet with the necessary cooperation of the
authorities. Only when Grijns, who continued' my investigations,
discovered that a certain bean, the "katjang idju" (Phaseolus
radiatus), has the protective and curative action in the case
of chickens, successful experiments - with this bean - were made
on man (Roelfsema, Hulshoff Pol, and Kiewiet de Jonge). It is,
however, obvious that this bean is of far less value as a staple
food than a suitable rice diet.

New encouragement then came from British
India (Braddon, Ellis, Fletcher, and Fraser & Stanton), on
the strength of which in 1910 the following resolution was drawn
up by the Far Eastern Association of Tropical Medicine meeting in
Manila:

"That in the opinion of this Association,
sufficient evidence has now been produced in support of the view
that beriberi is associated with the continuous consumption of
white (polished) rice as the staple article of diet, and that the
Association accordingly desires to bring this matter to the
notice of the various Governments concerned."

And in Hong Kong, 1912:

"That the accuracy of the opinion of the
Association, recorded in 1910, has received further and more
complete confirmation by investigators in Japan, China, French
Indo-China, the Philippine Islands, Siam, Netherlands India, the
Straits Settlements and the Federated Malay States, namely that
beriberi..."

Experiments on animals were naturally also
used in order to trace the distribution of the antineuritic
principle in living organisms. Numerous animal and vegetable
foodstuffs which are more or less rich in this principle are
listed in the literature on the subject. In practice this is of
the greatest importance, since here too it has been found that
the vitamin-rich foodstuffs can be used successfully to combat
human beriberi. Concentrated extracts of these have also been
prepared and these likewise have a pronounced curative action
both against polyneuritis in birds and against beriberi.

Until a short while ago, however, no one
had succeeded in extracting the active principle reliably and in
pure form from these initial materials, although indeed efforts
to do so were not wanting. And I was particularly delighted when
a few years ago Jansen and Donath were able to report from the
laboratory in Batavia - now a splendid improvement on my old
workshop - that they had isolated the antineuritic vitamin from
rice bran. It is a crystalline substance, obtained in the form of
a hydrochloride, an analysis of which gives approximately the
formula.

With this substance they conducted
experiments in preventive feeding with rice birds and pigeons,
and they found that an addition of 2 mg per 1 kg polished rice,
i.e. in the ratio of 1:500,000, is sufficient to give protection
against polyneuritis.

They sent me approximately 40 mg,
sufficient to carry out not only preventive but also curative
experiments on pigeons and young cocks. I was able to confirm
that such a minute addition gives protection and - which, indeed,
could not have been expected otherwise - also has curative
power.

Accordingly the human requirement of
antineuritic vitamin can be estimated at 1-2 mg per day.

* As Professor
Eijkman has been prevented by ill health from coming to Stockholm
to deliver his Nobel Lecture, he has very kindly sent the text to
the Editor of Les Prix Nobel for publication.